An open label positron emission tomography (PET) imaging study using 89Zirconium to investigate the biodistribution of anti-HER3 monoclonal antibody (mAb) GSK2849330 and characterize its dose receptor occupancy relationship in subjects with advanced HER3-positive solid tumors

The HER family of receptor tyrosine kinases is comprised of HER1 (EGFR), HER2
(ErbB2), HER3 (ErbB3) and HER4 (ErbB4). HER3 is capable of potent signaling
through the PI3K pathway leading to proliferation.
Monoclonal antibodies offer an ideal means of blocking both ligand dependent
and independent signaling as well as targeting cells over-expressing HER3 for
destruction. To this end GSK2849330, a monoclonal antibody specific to HER3, is
being developed. A FTIH study is being undertaken to assess the safety,
tolerability and pharmacokinetics of GSK2849330 as well as looking for
preliminary evidence of target engagement in subjects with advanced HER3
positive tumors. An understanding of the distribution of GSK2849330 into tumor
tissue and its interaction with HER3 would help to determine an optimal dose
level to be taken forward for further clinical development.
PET scanning is both quantitative and capable of assessing sites throughout the
body. Labeling antibodies with the radionuclide 89Zr allows them to be tracked
by PET scanning. The half-life of 89Zr is 3.3 days. The information from the
PET scanning will help to select a suitable dose to take forward for further
development of GSK2849330.

To measure in vivo biodistribution of 89Zirconium labeled GSK2849330 and
characterize its dose receptor occupancy relationship in subjects with advanced
HER3 positive solid malignancies.

Open label imaging study. Subjects will be screened for HER3 status. Only HER3
positive patients will be eligible.
Part 1: primarily in vivo biodistribution (3 weeks; 89 Zirconium labeling of
GSK2849330 to enable PET-CT scanning); Part 2: primarily to assess safety
(infusions with GSK2849330 every 1, 2 or 3 weeks). Treatment until disease
progression or severe toxicity (which ever comes first).
15 subjects.
Study in NL only.

Two doses 89Zr labeled GSK2849330 and unlabelled GSK2849330.

Risk: adverse events of study treatment.
Burden:
Visits: prescreening (0-1), screening (1), part 1 (4, 2-13 h), part 2 every 1,
2 of 3 weeks (until progression, 2-6 h), final visits (2, 1-5 h).
Infusions:
Labeled (2, during part 1), not labeled (0-2 during part 1, every 1, 2 or 3
weeks during part 2).
Tests:
Possibly tumor biopsy during prescreening (in case no/not enough archived tumor
material present).
Physical examination screening, every 3-4 weeks during part 2.
Blood tests during every visit (approx. 2-50 ml per visit).
ECG screening, part 1 2 visits, part 2 every 3-4 weeks.
Echocardiogram/MUGA-scan screening, part 2 every 8-10 weeks.
PET-CT scan max. 5 during part 1.
Scan for tumor measurements screening, 1 during part 1 and every 8-12 weeks
during part 2.
Optional: extra PET-scan during part 1.

The subject may be asked for permission that one or some employees from or on
behalf of the sponsor may attend some tests and procedures for monitoring
purposes. The subject is free to consent or to refuse.

Regimen for scans with 89 zirconium:
In principle the best measures during the first week after administration are
keeping at a distance and having physical contact as briefly as possible.
- Children under the age of 10 years should be kept at a distance as much as
possible and hugging (physical contact) should be limited to 3 times 30 minutes
per day *).
- Pregnant women should stay at a distance (> 1 meter).
- With regard to sleeping with the partner: keep as much distance as possible.
- Practice adequate hygiene: e.g. males should urinate when being seated, wash
your hands etc.
*) At 50 MBq: max 4 times 30 minutes, at 37 MBq max 5 times 30 minutes.